Tumor-selective response to antibody-mediated targeting of alphavbeta3 integrin in ovarian cancer.
The alpha(v)beta(3) integrin is expressed on proliferating endothelial cells and some cancer cells, but its expression on ovarian cancer cells and its potential as a therapeutic target are unknown. In this study, expression of the alpha(v)beta(3) integrin on ovarian cancer cell lines and murine endothelial cells was tested, and the effect of a fully humanized monoclonal antibody against alpha(v)beta(3), Abegrin (etaracizumab), on cell invasion, viability, tumor growth, and the Akt pathway were examined in vitro and in vivo. We found that etaracizumab recognizes alpha(v)beta(3) on the ovarian cancer cell lines SKOV3ip1, HeyA8, and A2780ip2 (at low levels) but not on murine endothelial cells. Etaracizumab treatment decreased ovarian cancer proliferation and invasion. In vivo, tumor-bearing mice treated with etaracizumab alone gave variable results. There was no effect on A2780ip2 growth, but a 36% to 49% tumor weight reduction in the SKOV3ip1 and HeyA8 models was found (P < .05). However, combined etaracizumab and paclitaxel was superior to paclitaxel in the SKOV3ip1 and A2780ip2 models (by 51-73%, P < .001) but not in the HeyA8 model. Treatment with etaracizumab was then noted to decrease p-Akt and p-mTOR in SKOV3ip1, but not in HeyA8, which is Akt-independent. Tumors resected after therapy showed that etaracizumab treatment reduced the proliferating cell nuclear antigen index but not microvessel density. This study identifies tumor cell alpha(v)beta(3) integrin as an attractive target and defines the Akt pathway as a predictor of response to function-blocking antibody.
Landen
Charles N
CN
Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Kim
Tae-Jin
TJ
Lin
Yvonne G
YG
Merritt
William M
WM
Kamat
Aparna A
AA
Han
Liz Y
LY
Spannuth
Whitney A
WA
Nick
Alpa M
AM
Jennnings
Nicholas B
NB
Kinch
Michael S
MS
Tice
David
D
Sood
Anil K
AK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D039302:Integrin alphaVbeta3 / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018709:Statistics, Nonparametric
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D039302:Integrin alphaVbeta3; C112567:etaracizumab